Mutations

PSEN2 M239T

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227076679 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to ACG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 8

Findings

This variant has been reported in three Chinese individuals with Alzheimer’s disease.

The first report was of a man diagnosed with posterior cortical atrophy, a clinical variant of sporadic early onset Alzheimer’s disease characterized by visual impairments (Li et al., 2021). The mutation was identified by whole-exome sequencing focusing on rare variants in 35 dementia-associated genes. The carrier developed progressive visual impairment and short-term memory loss at age 59. His initial symptoms were object agnosia, right-left confusion, and impaired episodic memory. His APOE genotype was APOE E3/E4. 

In addition, two women with AD were found to carry this mutation (Jiao et al., 2021, Mao et al., 2021). One was from a large cohort study in South China in which 14 genes associated with neurodegenerative dementias from 1795 patients were sequenced (Jiao et al., 2021). Her age at onset was 50 years and her APOE genotype was APOE E3/E4. She had no known family history of AD. Memory impairment was the only clinical phenotype reported. The other AD carrier also presented with memory loss with an age at onset of 47 years (Mao et al., 2021). This carrier had a family history of dementia.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, Oct 2021).

Neuropathology
Neuropathological data are unavailable, but brain imaging information is available for two carriers. In the carrier with posterior cortical atrophy, brain MRI showed bilateral parietal and occipital cortex atrophy and brain 18F-FDG-PET suggested hypometabolism in parietal, temporal, and occipital cortices. Florbetapir F18 positron emission tomography (AV-45-PET) revealed extensive Aβ deposition (Li et al., 2021).

The other carrier also had brain atrophy, but only of the parietal lobe. This mutation carrier had cerebrospinal fluid biomarker levels consistent with AD (Mao et al., 2021).

Biological Effect
The biological effects of this variant are unknown, but several in silico algorithms predicted it was damaging (Li et al., 2021, Mao et al., 2021) and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021). Li and colleagues classified this mutation as likely pathogenic.

Last Updated: 25 Oct 2021

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References

Paper Citations

  1. . Novel PSEN1 and PSEN2 Mutations Identified in Sporadic Early-onset Alzheimer Disease and Posterior Cortical Atrophy. Alzheimer Dis Assoc Disord. 2021 Jul-Sep 01;35(3):208-213. PubMed.
  2. . The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
  3. . Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Novel PSEN1 and PSEN2 Mutations Identified in Sporadic Early-onset Alzheimer Disease and Posterior Cortical Atrophy. Alzheimer Dis Assoc Disord. 2021 Jul-Sep 01;35(3):208-213. PubMed.
  2. . The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
  3. . Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. PubMed.

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